The role of the palmitoylation site of the A Disintegrin And Metalloprotease 10 (ADAM10)
The A Disintegrin and Metalloprotease 10 (ADAM10) has been recognized as a pivotal player in various (patho)physiological processes, encompassing neurodevelopment and diseases like Alzheimer's disease and cancer. Despite considerable knowledge about ADAM10's functions, investigations into its regulation remain limited. One aspect of interest is ADAM10's potential palmitoylation, a reversible posttranslational modification occurring on cysteine residues of proteins. In the present work, the significance of ADAM10's palmitoylation on its function and biochemistry was elucidated. Through techniques like acyl-resin capture assays, the palmitoylation of ADAM10 was confirmed. Interestingly, palmitoylation did not affect ADAM10 expression levels but possibly influenced its transport to the cell surface, where a palmitoylation-deficient mutant was labelled less. Further, the study provides evidence for a link between ADAM10 autoproteolysis and palmitoylation since impairment of either process led to altered generation of ADAM10's c-terminal fragment. This finding supports the conclusion that ADAM10's palmitoylation is important for its autoproteolytic activity. Investigations into ADAM10's shedding activity revealed potential effects of palmitoylation on the cleavage of distinct substrates. While the shedding of APP was reduced in cells expressing the palmitoylation deficient ADAM10 mutant, no significant impact was observed for N-cadherin shedding. Additionally, the study explored ADAM10's interactions with proteins like SAP-97 and AP-2, known regulators of ADAM10, with preliminary results suggesting potentially altered binding affinity due to palmitoylation. In conclusion, ADAM10 is S-palmitoylated. This palmitoylation seems to promote its expression at the cell surface and the generation of ADAM10 C-terminal fragments. Additionally, the palmitoylation may modulate the shedding of distinct substrates such as APP.
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